BACKGROUND The cyclin‐dependent kinase inhibitor p16INK4a is strongly and consistently overexpressed in all human papillomavirus (HPV)‐associated cancers. Therefore, the authors hypothesized that p16INK4a may be a vaccine target antigen for HPV‐associated cancers. To test this hypothesis, the authors performed a phase 1/2a first‐in‐human trial to evaluate the safety and immunogenicity of a p16INK4a‐based peptide vaccine. METHODS A total of 26 patients with different, advanced, p16INK4a‐overexpressing, HPV DNA‐positive cancers were included after the completion of standard treatment. According to protocol, 12 subcutaneous injections of a p16INK4 peptide (P16_37‐63) mixed in a water‐in‐oil emulsion with immunoadjuvant activity (Montanide ISA‐51 VG) were administered over a 6‐month period. RESULTS A total of 20 patients received at least 4 injections and were evaluable for immune responses against P16_37‐63. Clusters of differentiation (CD) 4 T cells were detected in 14 of 20 patients (3 of whom had preexisting CD4 T cells before vaccination), CD8 T cells were detected in 5 of 20 patients, and antibodies were detected in 14 of 20 patients (1 of whom had preexisting antibodies). No suspected unexpected serious adverse reaction or serious adverse drug reaction was documented. All reported serious adverse events were expected and not considered to be related to study therapy. None of the patients discontinued trial participation due to unacceptable toxicities and no dose‐limiting toxicities occurred. Tumor response could be assessed in 14 patients. Of these, 9 patients (64%) had stable disease as their best overall response and 5 patients (36%) developed progressive disease. CONCLUSIONS Vaccination with the p16INK4a‐derived peptide P16_37‐63 appears to induce cellular and humoral immune responses and does not cause severe toxicities. The results of the current study pave the way for the further clinical development of p16INK4a‐based cancer immunotherapeutics. Cancer 2016;122:1425–1433. © 2016 American Cancer Society.

No abstract

The obesity paradox, the controversial finding that obesity promotes disease development but protects against sequelae in patients, has been observed in venous thromboembolism (VTE). The aim of this investigation was to identify a body mass–related proteomic signature in VTE patients and to evaluate whether this signature mediates the obesity paradox in VTE patients. Data from the Genotyping and Molecular Phenotyping in Venous ThromboEmbolism Project, a prospective cohort study of 693 VTE patients, were analyzed. A combined end point of recurrent VTE or all-cause death was used. Relative quantification of 444 proteins was performed using high-throughput targeted proteomics technology. Measurements were performed in samples collected during the acute VTE event and at 12-month follow-up. An 11-protein signature (CLEC4C, FABP4, FLT3LG, IL-17C, LEP, LYVE1, MASP1, ST2, THBS2, THBS4, TSLP) for body mass in VTE patients was identified. The signature did not significantly mediate the obesity paradox (change in hazard ratio [HR]: 0.04; likelihood ratio test of nested models = 7.7; P = .74), but its main constituent protein, leptin, was inversely associated with recurrent VTE or death (adjusted HR [95% confidence interval] per standard deviation increase: 0.66 [0.46-0.94]). This relationship was significantly (P = .007) modified by markers of leptin resistance (ie, high body mass index and high circulating matrix metalloproteinase-2 levels). Although the signature did not substantially explain the obesity paradox, leptin appears to be protective against disease recurrence and death in VTE patients. This protective effect was abrogated under conditions of leptin resistance and hence was unrelated to the obesity paradox.